Herbs and dietary supplements are among the most commonly used complementary or alternative medical (CAM) therapies in the United States. As bone disorders become more prevalent in the aging population, a question that remains to be answered is whether botanical extracts, like ginger, could be useful dietary supplements in the treatment or prevention of common bone disorders. In metabolic bone disease, the cellular pathways that regulate the resorption or degradation of old bone and the formation of new bone become imbalanced such that resorption overtakes formation, weakening or impairing skeletal system function. Rheumatoid arthritis (RA) and osteoporosis are metabolic bone disorders in which bone destruction is mediated through activation of the receptor activator of NF-kB (RANK) pathway, the final common pathway for bone resorption. Preliminary data indicate that well characterized crude ginger extracts are able to inhibit bone loss in peri-articular bone in an animal model of RA through the inhibition of the RANK pathway. I therefore propose to verify ginger's efficacy as a bone-protective agent and elucidate the mechanism of ginger's effect on bone in two models of metabolic bone disease, RA and postmenopausal osteoporosis. In the streptococcal cell wall (SCW)-induced arthritis model for RA, female Lewis rats will be treated with vehicle or ginger extracts, and monitored for arthritic bone loss. Endpoints of analysis include bone mineral density (BMD) by dual energy x-ray absorptometry (DXA), serum markers for bone turnover, bone histomorphometry, changes in articular gene expression by gene array, verification of changes in expression of physiologically important genes by real-time reverse transcription PCR, and quantification of protein levels of ginger-regulated genes. In the ovariectomy (OVX) model of postmenopausal osteoporosis, female Sprague Dawley rats will undergo sham-operation or OVX, and then be treated with either vehicle or ginger extracts. In addition to previously named endpoints, bone micro-computed tomography (uCT) and mechanical bone strength will also be evaluated in the OVX study. Finally, specific sub-fractions of crude ginger extract (gingerols and essential oils) will be tested to determine their relative efficacy and mechanism of action in inhibiting osteoclast differentiation in a primary cell culture. The use of ginger for the prevention and treatment of debilitating metabolic bone disease is an exciting possibility considering its current availability as a dietary supplement. However, rigorous scientific evidence supporting its use for this purpose is lacking. The studies proposed here intend to address this important clinical and public health issue.